Transcriptional dysregulation in L-DOPA-induced dyskinesia

Sammanfattning: This study explores the role of transcriptional regulation important in the development of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. In patients with Parkinson’s disease, dyskinesia is one of the most difficult complications of the DA-replacement therapy by L-DOPA. The underlying mechanisms are still unknown, but a role of abnormal striatal plasticity has been proposed. The transcription factor cyclic AMP response element-binding protein (CREB) is believed to play a key role in DA receptor-mediated gene expression and neuroplasticity. This thesis demonstrates that the requirement of CREB depends on the experimental paradigm. CREB was required for both basal and cocaine-induced gene expression of c-Fos, FosB/?FosB, and prodynorphin mRNA (PDyn). But more importantly, CREB was not required for L-DOPA to induce the same genes in the DA-denervated striatum. An analysis of DNA-protein interactions showed that the transcription factors ?FosB and JunD appeared to supersede CREB in the binding to regulatory elements of the PDyn gene. The functional significance of ?FosB and JunD was studied using an antisense approach, whereby a local reduction of either ?FosB or JunD in the striatum was obtained. Antisense-mediated knockdown of ?FosB or JunD demonstrated that these transcription factors are causally linked with both PDyn gene expression and the development of dyskinesia in the rat model of Parkinson’s disease. A comparative analysis of FosB/?FosB and JunD at both the mRNA and protein levels disclosed a remarkably similar pattern of changes after acute and chronic L-DOPA treatment. First, junD and fosB/?fosB mRNA expression was induced by acute L-DOPA administration but declined upon repeated treatment. Second, the most prominent upregulation at the protein level was seen after chronic but not acute L-DOPA treatment. This effect was clearly dissociated from the changes in gene expression and led us to propose a new model of ?FosB/JunD induction on the gene and protein level, predicting that repeated administrations of L-DOPA progressively attenuate the transcription of the fosB and junD genes, while the respective proteins accumulate over time probably due to a lack of degradation. The findings of this thesis have implications for the development of therapies that minimize the motor complications of antiparkinsonian medications.